The precision of vision is thought to be anchored by selective response features of neurons in the visual pathway, by detailed representations of these features, and by precise relationships between the representations. Neurons in primary visual cortex (V1) are selective for multiple features of visual stimuli, for example orientation and spatial frequency, and are arranged into maps with orderly progression of feature preferences. The cellular resolution at which multiple feature maps and their relationships exist is unclear. We propose to investigate the details of map organization at the level of individual neurons in V1, using two photon imaging of calcium indicators. The technique allows an unprecedented combination of spatial resolution and coverage density, which will enable us to describe the stimulus feature representations of all individual neurons in a cortical volume and examine specific proposed relationships between these representations. Furthermore, there is growing evidence that astrocytes, which constitute over half of the cells in the human brain, have unique functions that not only derive from neuronal responses and representations but may also shape them. In addition, astrocytes are suspected to have a key role in the translation of neuronal activity into vascular and metabolic changes, the readout of which is a crucial component of many imaging modalities in neuroscience and medicine. Novel approaches, including specific cellular markers, optical probes of cellular function and structure, viral expression of fluorescent proteins, and genetically engineered mice with optical reporters of activity-dependent genes, provide new ways to examine the cooperative roles of neurons and astrocytes in cortical organization and function. We propose to use these approaches in combination with in vivo two-photon calcium imaging of cells in V1, optical imaging of intrinsic signals, in vivo structural imaging of spines, pharmacological manipulations, and electrophysiological recording, to examine the visual response properties, feature selectivity and feature representation of astrocytes. We will dissect the influence of astrocytes on particular components of signals that enable intrinsic optical imaging (and fMRI), and examine mechanisms by which astrocytes influence neurons, assayed by the development, and adult plasticity, of orientation selectivity. Together, these experiments will provide an extraordinarily detailed view of the representation of visual features in the cortex, and the interactions between neurons and astrocytes that underlie these representations. From a broader perspective, astrocytes are strongly implicated in a number of pathological conditions in the brain, including epilepsy, ischemia/stroke and hepatic encephalopathy. Understanding the function of astrocytes within a well-defined cortical circuit will go a long way towards defining early signatures of malfunction, developing a mechanistic understanding of the role of astrocytes in these pathological states, and suggesting strategies for their treatment. Significance: Astrocytes, which make up over half the cells in the human brain, are known to be integral to the maintenance of neuronal metabolism through their interactions with the vasculature of the brain, and have been linked to several neuropathological conditions. In a major paradigm shift, they have recently been shown to interact cooperatively with neurons. The planned experiments will examine visual responses and representations of neurons and astrocytes in the visual cortex and clarify the role of astrocytes in shaping neuronal circuits, providing a new avenue for the development of therapeutic tools against a variety of diseases including stroke and epilepsy.

National Institute of Health (NIH)
National Eye Institute (NEI)
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Cognitive Neuroscience Study Section (COG)
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Steinmetz, Michael A
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Massachusetts Institute of Technology
Schools of Arts and Sciences
United States
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